Cancer is one of the leading causes of death in the developed world. Approximately one-quarter of the deaths in the United States in 1997 were due to cancer, making it the second most common cause of death after heart disease. Accordingly, development of new and effective treatments for cancer is a high priority for health care researchers.
Cancer is often treated by using chemotherapy to selectively kill or hinder the growth of cancer cells, while having a less deleterious effect on normal cells. Chemotherapeutic agents often kill rapidly dividing cells, such as cancer cells; cells which are dividing less rapidly are affected to a lesser degree. Other agents, such as antibodies attached to toxic agents, have been evaluated for use against cancers. These agents target the cancer cells by making use of a characteristic specific to the cancer, for example, higher-than-normal rates of cell division, or unique antigens expressed on the cancer cell surface.
Polyamines and polyamine analogs have been proposed as anti-cancer agents. Natural polyamines, e.g., spermidine, norspermidine, homospermidine, 1,4-diaminobutane (putrescine), and spermine, are simple aliphatic amines produced in eukaryotic cells by a highly regulated metabolic apparatus. Polyamine levels and the activity of the polyamine biosynthetic apparatus tend to be high in dividing mammalian cells and low in quiescent cells. Populations of cells depleted of their polyamine content stop growing and may die. Janne et al. (1978) A. Biochim. Biophys. Acta. 473:241 and Pegg et al. (1982) Ami. J. Cell. Physiol. 243:212–221. Polyamines are reviewed in Morgan (1998) Methods. Mol. Biol. 79:3–30.
Several lines of evidence indicate that polyamines, particularly spermidine, are required for cell proliferation: (i) they are found in greater amounts in growing than in non-growing tissues; (ii) prokaryotic and eukaryotic mutants deficient in polyamine biosynthesis are auxotrophic for polyamines; and (iii) inhibitors specific for polyamine biosynthesis also inhibit cell growth. Despite this evidence, the precise biological role of polyamines in cell proliferation is uncertain. It has been suggested that polyamines, by virtue of their charged nature under physiological conditions and their conformational flexibility, might serve to stabilize macromolecules, such as nucleic acids, by anion neutralization. Hafner et al. (1979) J. Biol. Chem. 254:12419; Pohjatipelto et al. (1981) Nature 293:475; Mamont et al. (1978) Biochem. Biophys. Res. Commun. 81:58; Bloomfield et al. (1981) in Polyamines in Biology and Medicine, Morris et al., Eds., Dekker, N.Y., pp. 183–205.
A treatment approach has been devised based on the observation that increases in the polyamine pool suppress polyamine biosynthesis. Porter et al. (1988) in Advances in Enzyme Regulation, Pergamon Press, pp. 57–79. This approach attempts to identify polyamine analogs which down-regulate polyamine biosynthesis, but which do not perform the polyamine functions required for cell growth. BESPM, a N-bis(ethyl) analog of spermine, has served as a model compound for this strategy. BESPM rapidly suppresses polyamine biosynthetic enzymes, depletes natural polyamine pools, and inhibits cell growth in vitro. Porter et al. (1987) Cancer Res. 47:2821–2825. In addition, BESPM suppresses polyamine uptake (Byers et al. (1990) J. Physiol. 142:460–467; and Kramer et al. (1993) J. Cell. Physiol. 115:399–407), and thus minimizes the ability of tumor cells to meet their polyamine requirement by taking them up from their environment. BESPM and related analogs also induce the polyamine metabolizing enzyme spermidine/spermine N1-acetyltransferase (SSAT) in certain human carcinoma cell lines.
BESPM and other polyamine analogs have been used, or proposed for use, in treating a large variety of diseases, including a number of different cancers. See International Patent Application WO 00/66587, and U.S. Pat. Nos. 5,889,061, 5,880,161, and 5,541,230. Polyamine analogs demonstrated, for example, potent antitumor activity against several melanoma cell lines and tumors in vitro (Porter et al. (1991) Cancer Res. 51:3715–3720; Shappell et al. (1992) Anticancer Res. 12:1083–1090) and in vivo using tumors growing as xenografts in athymic mice (Bernacki et al. (1992) Cancer Res. 52:2424–2430; Porter et al. (1993) Cancer Res. 53:581–586). Potent antitumor activity of bis-ethyl spermine analogs has also been demonstrated for pancreatic cancer cell lines in vitro (Chang et al. (1992) Cancer Chemother. Pharmacol. 30:183–188) and in vivo (Chang et al. (1992) Cancer Chemother. Pharmacol. 30:179–182). Polyamine analogs have also been suggested for use in treating brain tumor therapy. Redgate et al. (1995) J. Neurooncol. 25:167–79. In addition to being useful against cancers of the brain, pancreas, and skin, polyamine analogs are also useful against cancers of the bladder, bone, breast, colon, digestive tract, lung and ovaries. Chang et al. (1993) J. Urol. 150:1293–7; Snyder et al. (1994) Anticancer Res. 14:347–56; Yuan et al. (1994) Biochem. Pharmacol. 47:1587–92; Davidson et al. (1993) Cancer Res. 53:2071–5; Berchtold et al. (1998) J. Cell. Physiol. 174:380–6; Porter et al. (1988) Adv. Exp. Med Biol. 250:677–90; U.S. Pat. Nos. 5,498,522 and 5,374,658. U.S. Pat. No. 5,498,522 presents the use of spermidine/spermine N1-acetyltransferase as a prognostic indicator of the efficacy of a polyamine analog against a malignant tumor.
Polyamine analogs have been used to treat cancer of the prostate )Mi et al. (1988) Prostate 34:51–60). Polyamines are produced in large amounts by the prostate gland and are abundant in the seminal fluid (Herr et al. (1984) Cancer 53:1294–8). Polyamine analogs such as BE-4444, BE-373, and BE-333 are particularly effective in inhibiting prostate xenograft tumors in nude mice; see Zagaja et al. (1998) Cancer Chem. Pharm. 41:505–512; Jeffers et al. (1997) Cancer Chem. Pharm. 40:172–179; Feuerstein et al. (1991) J. Cell. Biochem. 46:37–47; and Marton et al. (1995) Ann. Rev. Pharm. Toxicol. 35:55–91.
Polyamines and their analogs can be administered alone or in conjunction with additional agents. For example, therapeutic polyamines can be administered along with 1,3-bis (2-chloroethyl)-1-nitrosourea. U.S. Pat. No. 5,541,230. In treating cancer, polyamines can be co-administered with various cytotoxic agents, including antineoplastic vinca alkaloids, antibiotics, antimetabolites, and platinum coordination complexes. U.S. Pat. No. 5,654,287.
It would be advantageous to develop novel polyamine analogs for use as anti-cancer therapies. This invention describes
All references cited herein are hereby incorporated by reference in their entirety.